Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China.
CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China.
J Exp Med. 2022 Sep 5;219(9). doi: 10.1084/jem.20210998. Epub 2022 Jul 25.
Astrocyte activation is associated with progressive inflammatory demyelination in multiple sclerosis (MS). The molecular mechanisms underlying astrocyte activation remain incompletely understood. Recent studies have suggested that classical neurotransmitter receptors are implicated in the modulation of brain innate immunity. We investigated the role of dopamine signaling in the process of astrocyte activation. Here, we show the upregulation of dopamine D2 receptor (DRD2) in reactive astrocytes in MS brain and noncanonical role of astrocytic DRD2 in MS pathogenesis. Mice deficient in astrocytic Drd2 exhibit a remarkable suppression of reactive astrocytes and amelioration of experimental autoimmune encephalomyelitis (EAE). Mechanistically, DRD2 regulates the expression of 6-pyruvoyl-tetrahydropterin synthase, which modulates NF-κB activity through protein kinase C-δ. Pharmacological blockade of astrocytic DRD2 with a DRD2 antagonist dehydrocorybulbine remarkably inhibits the inflammatory response in mice lacking neuronal Drd2. Together, our findings reveal previously an uncharted role for DRD2 in astrocyte activation during EAE-associated CNS inflammation. Its therapeutic inhibition may provide a potent lever to alleviate autoimmune diseases.
星形胶质细胞的激活与多发性硬化症（MS）中进行性炎症性脱髓鞘有关。星形胶质细胞激活的分子机制仍不完全清楚。最近的研究表明，经典神经递质受体参与了脑固有免疫的调节。我们研究了多巴胺信号在星形胶质细胞激活过程中的作用。在这里，我们展示了 MS 大脑中反应性星形胶质细胞中多巴胺 D2 受体（DRD2）的上调，以及星形胶质细胞 DRD2 在 MS 发病机制中的非典型作用。缺乏星形胶质细胞 Drd2 的小鼠表现出反应性星形胶质细胞的显著抑制和实验性自身免疫性脑脊髓炎（EAE）的改善。在机制上，DRD2 调节 6-丙酮酰四氢蝶呤合酶的表达，通过蛋白激酶 C-δ 调节 NF-κB 活性。用 DRD2 拮抗剂脱氢柯里布林阻断星形胶质细胞 DRD2 的药理学抑制，可显著抑制缺乏神经元 Drd2 的小鼠的炎症反应。总之，我们的研究结果揭示了 DRD2 在 EAE 相关中枢神经系统炎症期间星形胶质细胞激活中的以前未知的作用。其治疗抑制可能为缓解自身免疫性疾病提供有力手段。
